Abstract PO3-13-04: The role of sphingolipids in cancer progression and its microenvironment in breast cancer patients

Abstract Background: Sphingosine-1-phosphate (S1P) is a lipid mediator, and although it is a lipid, it acts as a signaling molecule similar to proteins by stimulating specific receptors. In the cell, ceramide (Cer), a component of the cell membrane, is converted to sphingosine (So), and So is phosphorylated by specific enzymes, named sphingosine kinases 1 and 2, to produce S1P. Based on the results of previous basic and translational researches, it is believed that S1P contributes to cell survival, and ceramide contributes to cell death, such as apoptosis, and that the balance of these sphingolipids regulates cell survival and death. Because sphingolipids are lipids, it is technically difficult to measure their concentration in patients, and their clinical significance has not yet been fully elucidated. The purpose of this study was to quantify sphingolipids in the blood of breast cancer patients and compare them with clinicopathological factors to determine their clinical significance. Methods: Among breast cancer patients who underwent surgery at our hospital from September 2019 to April 2021, 118 cases were included, excluding breast cases with ductal carcinoma in situ and cases who received neoadjuvant chemotherapy. Plasma was collected from preoperative breast cancer patients, and cryopreserved samples were subjected to lipidomics analysis by mass spectrometry. As sphingolipids, So, dihydro-So (DHSo), S1P, DHS1P, and Cer (C14:0, C16:0, C18:0, C18:1, C20:0, C22:0, C24:0, C24:1, C26:0, C26:1, total Cer) levels were quantified, and S1P/Cer ratios were determined, and those data were compared with clinicopathological factors. Results: The median age of the 118 patients was 58 years (range 29-86), and the types of breast cancer included 103 luminal, 8 HER2-positive, and 7 triple-negative cases. No significant associations were found between age, subtype, and the levels of any of the sphingolipids. Compared to the negative group, the positive lymphatic invasion group had higher So and DHSo levels, and S1P/Cer ratios (p=0.0262, p=0.0167, and p=0.002, respectively) and lower total Cer (p=0.0401). Total Cer was lower in the vascular invasion-positive group than in the negative group (p=0.0365). The lymph node-positive group tended to show higher C24:0 levels (p=0.0867). No association was found between tumor diameter, nuclear grade, or tissue grade and sphingolipid levels. Interestingly, analysis of the association between sphingolipids and tumor-infiltrating lymphocytes (TILs) showed significant differences: So and DHSo levels, and S1P/ceramide ratio were significantly higher in the TILs-high group (p=0.0063, p=0.0011, and p=0.0171, respectively). DHS1P also tended to be higher with higher TILs (p=0.072), and S1P showed a similar trend, although not statistically significant. Conclusion: Our data revealed that plasma sphingolipid concentrations were significantly associated with lymphatic invasion and TILs. These findings suggest that sphingolipids may be involved in shaping the tumor microenvironment in breast cancer patients. Citation Format: Akira Hattori, Masayuki Nagahashi, Aoi Oshiro, Ayumu Mitsuyoshi, Haruka Kanaoka, Ayako Bun, Reiko Fukui, Yukie Fujimoto, Tomoko Higuchi, Arisa Nishimukai, Keiko Murase, Yuichi Takatsuka, Yasuo Miyoshi. The role of sphingolipids in cancer progression and its microenvironment in breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-04.